Sedentary lifestyle is a prevalent, modifiable risk factor for cardiovascular disease (CVD), which is the number one cause of death in the United States. Exercise training is known to decrease cardiovascular risk through decreasing blood pressure, improving lipids, and decreasing adiposity, but additional risk reduction is observed beyond these mechanisms. Understanding how exercise improves cardiovascular health as well as the effectiveness of structured exercised program for cardiovascular risk reduction for different populations would be helpful for clinical guidelines and public health planning. We seek to address these questions using two clinical trials conducted at the Johns Hopkins General Clinical Research Center. Both research studies randomized sedentary adults to either an identical 6-month aerobic and strength training intervention or usual care. The first study population (SHAPE) included persons with mild hypertension and the second study (SHAPE2) included persons with mild hypertension and type 2 diabetes (T2DM). We propose to use the two studies and benefit from the excellent study design and premium measures of traditional cardiovascular risk factors as well as exercise and fitness to answer this important public health question. In the proposed grant, we plan to: 1. Examine the impact of structured exercise on endothelial function. To carry out this aim we will reanalyze data from brachial artery ultrasound obtained from SHAPE using edge detection software. We will also measure novel biomarkers of endothelial function using frozen serum samples from SHAPE2. 2. Determine whether exercise improves left ventricular diastolic function by analyzing tagged cardiac magnetic resonance imaging from SHAPE and SHAPE2 to estimate left ventricular (LV) diastolic function. 3. Using data from maximal exercise stress tests, determine the importance of changes in fitness for predicting changes in markers of CVD. 4. Analyze data from hepatic magnetic resonance spectroscopy estimating the level of hepatic steatosis in SHAPE2 to examine the relationship between hepatic fat to parameters of cardiac function, CVD risk factors and measures of body composition and fitness. Using these unique datasets we can answer questions that go beyond the original aims of SHAPE and SHAPE2. We will study the impact of exercise and changes in cardio-respiratory fitness on several CVD markers and hepatic fat in mildly hypertensive persons with and without T2DM. These analyses will advance our knowledge of the cardiovascular effects of exercise training and could affect national recommendations on exercise and fitness. PUBLIC HEALTH RELEVANCE: The proposed research will further describe and quantify the effects of exercise on markers of cardiovascular disease in sedentary adults with cardiovascular risk factors. We will take advantage of two preexisting NIH- funded randomized controlled clinical trials with structured exercise interventions in patients with mild hypertension and type 2 diabetes and measure the impact of exercise and changes in fitness on state-of-the-art serologic and physiologic measures of cardiovascular disease. The results will be used to improve our knowledge of the direct effect of exercise on the cardiovascular system and could inform clinical guidelines on exercise. 1